Association Between Change in BMD and Fragility Fracture in Women and Men

Our objective was to estimate the relationship between longitudinal change in BMD and fragility fractures. We studied 3635 women and 1417 men 50–85 yr of age in the Canadian Multicentre Osteoporosis Study who had at least two BMD measurements (lumbar spine, femoral neck, total hip, and trochanter) within the first 5 yr of the study and fragility fractures (any, main, forearm/wrist, ribs, hip) within the first 7 yr. Multiple logistic regression was used to model the relationship between baseline BMD, BMD change, and fragility fractures. We found that, among nonusers of antiresorptives, independent of baseline BMD, a decrease of 0.01 g/cm²/yr in total hip BMD was associated with an increased risk of fragility fracture with ORs of 1.15 (95% CI: 1.01; 1.32) in women and 1.34 (95% CI: 1.02; 1.78) in men. The risk of fragility fractures in subgroups such as fast losers and those with osteopenia was better estimated by models that included BMD change than by models that included baseline BMD but excluded BMD change. Although the association between baseline BMD and fragility fractures was similar in users and nonusers of antiresorptives, the association was stronger in nonusers compared with users. These results show that BMD change in both men and women is an independent risk factor for fragility fractures and also predicts fracture risk in those with osteopenia. The results suggest that BMD change should be included with other variables in a comprehensive fracture prediction model to capture its contribution to osteoporotic fracture risk.     

Identification of a Linkage Disequilibrium Block in Chromosome 1q Associated With BMD in Premenopausal White Women

Osteoporosis is a complex disease with both genetic and environmental risk factors. A major determinant of osteoporotic fractures is peak BMD obtained during young adulthood. We previously reported linkage of chromosome 1q (LOD = 4.3) with variation in spinal areal BMD in healthy premenopausal white women. In this study, we used a two‐stage genotyping approach to identify genes in the linked region that contributed to the variation of femoral neck and lumbar spine areal BMD. In the first stage, 654 SNPs across the linked region were genotyped in a sample of 1309 premenopausal white women. The most significant evidence of association for lumbar spine (p = 1.3 × 10^?6) was found with rs1127091 in the GATAD2B gene. In the second stage, 52 SNPs around this candidate gene were genotyped in an expanded sample of 1692 white women. Significant evidence of association with spinal BMD (p < 10^?5), and to a lesser extent with femoral neck BMD, was observed with eight SNPs within a single 230‐kb linkage disequilibrium (LD) block. The most significant SNP (p = 3.4 × 10^?7) accounted for >2.5% of the variation in spinal BMD in these women. The 230‐kb LD block contains 11 genes, but because of the extensive LD, the specific gene(s) contributing to the variation in BMD could not be determined. In conclusion, the significant association between spinal BMD and SNPs in the 230‐kb LD block in chromosome 1q indicates that genetic factor(s) in this block plays an important role in peak spinal BMD in healthy premenopausal white women.     

BMD in Population‐Based Adult Women Is Associated With Socioeconomic Status

With few exceptions, an inverse relationship exists between social disadvantage and disease. However, there are conflicting data for the relationship between socioeconomic status (SES) and BMD. The aim of this study was to assess the association between SES and lifestyle exposures in relation to BMD. In a cross‐sectional study conducted using 1494 randomly selected population‐based adult women, we assessed the association between SES and lifestyle exposures in relation to BMD. BMD was measured at multiple anatomical sites by DXA. SES was determined by cross‐referencing residential addresses with Australian Bureau of Statistics 1996 census data for the study region and categorized in quintiles. Lifestyle variables were collected by self‐report. Regression models used to assess the relationship between SES and BMD were adjusted for age, height, weight, dietary calcium, smoking, alcohol consumption, physical activity, hormone therapy, and calcium/vitamin D supplements. Unadjusted BMD differed across SES quintiles (p < 0.05). At each skeletal site and SES index, a consistent peak in adjusted BMD was observed in the mid‐quintiles. Differences in adjusted BMD were observed between SES quintiles 1 and 4 (3–7%) and between quintiles 5 and 4 (2–7%). At the spine, the maximum difference was observed (7.5%). In a subset of women, serum 25(OH)D explained a proportion of the association between SES and BMD (difference remained up to 4.2%). Observed differences in BMD across SES quintiles, consistent across both SES indices, suggest that low BMD may be evident for both the most disadvantaged and most advantaged.     

Genetic Analyses in a Sample of Individuals With High or Low BMD Shows Association With Multiple Wnt Pathway Genes

Using a moderate‐sized cohort selected with extreme BMD (n = 344; absolute value BMD, 1.5–4.0), significant association of several members of the Wnt signaling pathway with bone densitometry measures was shown. This confirms that extreme truncate selection is a powerful design for quantitative trait association studies of bone phenotypes. Introduction : Although the high heritability of BMD variation has long been established, few genes have been conclusively shown to affect the variation of BMD in the general population. Extreme truncate selection has been proposed as a more powerful alternative to unselected cohort designs in quantitative trait association studies. We sought to test these theoretical predictions in studies of the bone densitometry measures BMD, BMC, and femoral neck area, by investigating their association with members of the Wnt pathway, some of which have previously been shown to be associated with BMD in much larger cohorts, in a moderate‐sized extreme truncate selected cohort (absolute value BMD Z‐scores = 1.5–4.0; n = 344). Materials and Methods : Ninety‐six tag‐single nucleotide polymorphism (SNPs) lying in 13 Wnt signaling pathway genes were selected to tag common genetic variation (minor allele frequency [MAF] > 5% with an r² > 0.8) within 5 kb of all exons of 13 Wnt signaling pathway genes. The genes studied included LRP1, LRP5, LRP6, Wnt3a, Wnt7b, Wnt10b, SFRP1, SFRP2, DKK1, DKK2, FZD7, WISP3, and SOST. Three hundred forty‐four cases with either high or low BMD were genotyped by Illumina Goldengate microarray SNP genotyping methods. Association was tested either by Cochrane‐Armitage test for dichotomous variables or by linear regression for quantitative traits. Results : Strong association was shown with LRP5, polymorphisms of which have previously been shown to influence total hip BMD (minimum p = 0.0006). In addition, polymorphisms of the Wnt antagonist, SFRP1, were significantly associated with BMD and BMC (minimum p = 0.00042). Previously reported associations of LRP1, LRP6, and SOST with BMD were confirmed. Two other Wnt pathway genes, Wnt3a and DKK2, also showed nominal association with BMD. Conclusions : This study shows that polymorphisms of multiple members of the Wnt pathway are associated with BMD variation. Furthermore, this study shows in a practical trial that study designs involving extreme truncate selection and moderate sample sizes can robustly identify genes of relevant effect sizes involved in BMD variation in the general population. This has implications for the design of future genome‐wide studies of quantitative bone phenotypes relevant to osteoporosis.     

Genome‐Wide Survey of Runs of Homozygosity Identifies Recessive Loci for Bone Mineral Density in Caucasian and Chinese Populations

Runs of homozygosity (ROHs), in which both parental alleles are identical, have been proposed to have recessive effects on multiple human complex diseases. Osteoporosis is a common complex disease characterized by low bone mineral density (BMD), which is highly heritable. And recessive loci that contribute to BMD variations have been identified. In this study, we performed a genome‐wide ROHs association study using our SNP array data from three GWAS samples including 4,900 subjects from Caucasian and Chinese populations. Significant results were further subjected to replication in 3,747 additional subjects. ROHs associated with BMD were also tested for associations with osteoporotic fractures in a GWAS fracture sample. Combining results from all the samples, we identified 697 autosomal regions with ROHs. Among these, we detected genome‐wide significant associations between BMD and 6 ROHs, including ROH1q31.3, 1p31.1, 3q26.1, 11q12.1, 21q22.1 and 15q22.3 (combined P = 6.29 × 10^‐5 ‐ 3.17 × 10^‐8). Especially, ROH1p31.1 was found to be associated with increased risk of osteoporotic hip fractures (odds ratio [OR] = 3.71, P = 0.032). To investigate the functional relevance of the identified ROHs, we performed cis‐expression quantitative trait locus (eQTL) analysis in lymphoblast cell lines. Three ROHs, including ROH1p31.1, 11q12.1, and 15q22.3, were found to be significantly associated with mRNA expression levels of their nearby genes (P_eQTL < 0.05). In summary, our findings reveal that ROHs could play as recessive‐acting determinants contributing to the pathogenesis of osteoporosis. Further molecular and functional studies are needed to explore and clarify the potential mechanism. © 2015 American Society for Bone and Mineral Research.     

Repeat Low‐Trauma Fractures Occur Frequently Among Men and Women Who Have Osteopenic BMD

Fracture risk assessment based solely on BMD has limitations. Additional risk factors include the presence of a previous low‐trauma fracture. We sought to quantify the fracture burden attributable to first versus repeat fracture. We studied 2179 men and 5269 women, 50–90 yr of age, participating in the Canadian Multicentre Osteoporosis Study (CaMos). We included all low‐trauma fractures that occurred over 8 yr of follow‐up and classified these as either first or repeat clinical low‐trauma fracture based on lifetime fracture history. Analyses were further stratified by sex, age, BMD risk categories (normal, osteopenia, osteoporosis), and vertebral deformity status. There were 128 fractures in men and 577 fractures in women. About 25% of fractures in men and 40% in women were repeat fractures. Just over one half of first fractures occurred in those with osteopenic BMD (58% in men, 54% in women). Just under one half of repeat fractures also occurred in those with osteopenic BMD (42% in men, 47% in women). The incidence of repeat fracture was, in most cases, nearly double, but sometimes nearly quadruple, the incidence of first fracture within a given BMD risk category in both men and women. Repeat fractures contribute substantially to overall fracture burden, and the contribution is independent of BMD. Furthermore, those with a combination of prior low‐trauma fracture and another risk factor were at especially high risk of future fracture.     

Leukocyte Telomere Length Is Not Associated With BMD,Osteoporosis, or Fracture in Older Adults: Results From the Health,Aging and Body Composition Study

Short leukocyte telomere length (TL), low BMD, and osteoporosis have been associated with increased inflammation. Previous reports suggest an association between TL, BMD, and osteoporosis in women. We sought to verify these associations and to determine whether TL is related to fracture in a cohort of older men and women. Participants included 2750 community‐dwelling older persons from the longitudinal Health, Aging, and Body Composition Study (Health ABC) in who average leukocyte TL was measured at baseline using qPCR. We used unconditional logistic regression to determine the association of TL with prevalent fracture, Cox proportional hazards regression for the association with 7‐yr incident fracture, and mixed linear models for the association with BMD, change in BMD, and the number of incident fractures. TL was negatively correlated with age, weight, fasting insulin, and fasting glucose in men and women, and additionally, with C‐reactive protein and IL‐6 in men. TL was not associated with BMD; change in BMD over 1, 3, or 5 yr; osteoporosis; baseline fracture; or 7‐yr incident fracture, before or after adjustment for age, race, smoking, and health characteristics. TL is not associated with BMD, osteoporosis, or fracture in older men or women in this sample.     

Reduced COX‐2 Expression in Aged Mice Is Associated With Impaired Fracture Healing

The cellular and molecular events responsible for reduced fracture healing with aging are unknown. Cyclooxygenase 2 (COX‐2), the inducible regulator of prostaglandin E₂ (PGE₂) synthesis, is critical for normal bone repair. A femoral fracture repair model was used in mice at either 7–9 or 52–56 wk of age, and healing was evaluated by imaging, histology, and gene expression studies. Aging was associated with a decreased rate of chondrogenesis, decreased bone formation, reduced callus vascularization, delayed remodeling, and altered expression of genes involved in repair and remodeling. COX‐2 expression in young mice peaked at 5 days, coinciding with the transition of mesenchymal progenitors to cartilage and the onset of expression of early cartilage markers. In situ hybridization and immunohistochemistry showed that COX‐2 is expressed primarily in early cartilage precursors that co‐express col‐2. COX‐2 expression was reduced by 75% and 65% in fractures from aged mice compared with young mice on days 5 and 7, respectively. Local administration of an EP4 agonist to the fracture repair site in aged mice enhanced the rate of chondrogenesis and bone formation to levels observed in young mice, suggesting that the expression of COX‐2 during the early inflammatory phase of repair regulates critical subsequent events including chondrogenesis, bone formation, and remodeling. The findings suggest that COX‐2/EP4 agonists may compensate for deficient molecular signals that result in the reduced fracture healing associated with aging.     

Genetic Hypercalciuric Stone‐Forming Rats Have a Primary Decrease in BMD and Strength

Kidney stone patients often have a decrease in BMD. It is unclear if reduced BMD is caused by a primary disorder of bone or dietary factors. To study the independent effects of hypercalciuria on bone, we used genetic hypercalciuric stone‐forming (GHS) rats. GHS and control (Ctl) rats were fed a low Ca (0.02% Ca, LCD) or a high Ca (1.2% Ca, HCD) diet for 6 wk in metabolic cages. All comparisons are to Ctl rats. Urine Ca was greater in the GHS rats on both diets. GHS fed HCD had reduced cortical (humerus) and trabecular (L₁–L₅ vertebrae) BMD, whereas GHS rats fed LCD had a reduction in BMD similar to Ctl. GHS rats fed HCD had a decrease in trabecular volume and thickness, whereas LCD led to a ～20‐fold increase in both osteoid surface and volume. GHS rats fed HCD had no change in vertebral strength (failure stress), ductibility (failure strain), stiffness (modulus), or toughness, whereas in the humerus, there was reduced ductibility and toughness and an increase in modulus, indicating that the defect in mechanical properties is mainly manifested in cortical, rather than trabecular, bone. GHS rat cortical bone is more mineralized than trabecular bone and LCD led to a decrease in the mineralization profile. Thus, the GHS rats, fed an ample Ca diet, have reduced BMD with reduced trabecular volume, mineralized volume, and thickness, and their bones are more brittle and fracture prone, indicating that GHS rats have an intrinsic disorder of bone that is not secondary to diet.     

In Vivo Genome‐Wide Expression Study on Human Circulating B Cells Suggests a Novel ESR1 and MAPK3 Network for Postmenopausal Osteoporosis

Introduction : Osteoporosis is characterized by low BMD. Studies have shown that B cells may participate in osteoclastogenesis through expression of osteoclast‐related factors, such as RANKL, transforming growth factor β (TGFB), and osteoprotegerin (OPG). However, the in vivo significance of B cells in human bone metabolism and osteoporosis is still largely unknown, particularly at the systematic gene expression level. Materials and Methods : In this study, Affymetrix HG‐U133A GeneChip arrays were used to identify genes differentially expressed in B cells between 10 low and 10 high BMD postmenopausal women. Significance of differential expression was tested by t‐test and adjusted for multiple testing with the Benjamini and Hochberg (BH) procedure (adjusted p ≤ 0.05). Results : Twenty‐nine genes were downregulated in the low versus high BMD group. These genes were further analyzed using Ingenuity Pathways Analysis (Ingenuity Systems). A network involving estrogen receptor 1 (ESR1) and mitogen activated protein kinase 3 (MAPK3) was identified. Real‐time RT‐PCR confirmed differential expression of eight genes, including ESR1, MAPK3, methyl CpG binding protein 2 (MECP2), proline‐serine‐threonine phosphatase interacting protein 1 (PSTPIP1), Scr‐like‐adaptor (SLA), serine/threonine kinase 11 (STK11), WNK lysine‐deficient protein kinase 1 (WNK1), and zinc finger protein 446 (ZNF446). Conclusions : This is the first in vivo genome‐wide expression study on human B cells in relation to osteoporosis. Our results highlight the significance of B cells in the etiology of osteoporosis and suggest a novel mechanism for postmenopausal osteoporosis (i.e., that downregulation of ESR1 and MAPK3 in B cells regulates secretion of factors, leading to increased osteoclastogenesis or decreased osteoblastogenesis).     

SIRT1/HERC4 Locus Associated With Bisphosphonate‐Induced Osteonecrosis of the Jaw: An Exome‐Wide Association Analysis

Osteonecrosis of the jaw (ONJ) is a rare, but serious drug side effect, mainly associated with the use of intravenous (iv) bisphosphonates (BPs). The purpose of this study was to identify genetic variants associated with ONJ in patients of European ancestry treated with iv BPs using whole‐exome sequencing (WES). The WES phase 1 included 44 multiple myeloma patients (22 ONJ cases and 22 controls) and WES phase 2 included 17 ONJ patients with solid tumors. Multivariable logistic regression analysis was performed to estimate the odds ratios (ORs) and 95% confidence intervals (CI), adjusting for age, sex, and principal components for ancestry. Meta‐analysis of WES phase 1 and 2 was performed to estimate the combined ORs. In silico analyses were then performed to identify expression quantitative loci (eQTL) single‐nucleotide polymorphisms (SNPs) that are in high linkage disequilibrium (LD) with the top SNPs. The associations of the potentially functional SNPs were replicated and validated in an independent case‐control study of 48 patients of European ancestry treated with iv BPs (19 ONJ cases and 29 controls). The top SNPs in the exome‐wide association meta‐analysis were two SNPs on chromosome 10: SIRT1 SNP rs7896005 and HERC4 SNP rs3758392 with identical OR of 0.07 (0.01–0.46; p = 3.83 × 10^?5). In the in silico functional analyses, two promoter region SNPs (rs7894483 and rs3758391) were identified to be in high LD with the index SNPs and are eQTLs for SIRT1 gene in whole blood in the GTEx database. The ORs were 0.30 (0.10–0.88), 0.26 (0.12–0.55), and 0.26 (0.12–0.55) for the WES top SNP rs7896005 and two promoter SNPs rs7894483 and rs3758391, respectively, in the replication sample. In summary, we identified the SIRT1/HERC4 locus on chromosome 10 to be associated with iv BP‐induced ONJ and two promoter SNPs that might be the potential genetic markers for this association. © 2017 The Authors.Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.     

Fibroblast Growth Factor 21 Is Associated With Bone Mineral Density,but not With Bone Turnover Markers and Fractures in Chinese Postmenopausal Women

Fibroblast growth factor 21 (FGF21) is a member of the endocrine FGF subfamily and an important metabolic regulator that has multiple beneficial effects on glucose homeostasis and lipid metabolism. However, it was unclear whether FGF21 would induce bone defects in humans. This study evaluated the associations of FGF21 levels, bone mineral density (BMD), osteoporotic fracture, and bone turnover marks (BTMs) in postmenopausal women. A total of 1342 postmenopausal Chinese Han women (511 cases of fragility fracture in the case group and 831 cases in nonfragility fracture group) were enrolled. Serum FGF21 concentration was measured by ELISA (Quantikine), serum calcium (Ca), phosphate (P), alkaline phosphatase, 25-hydroxyvitamin D, parathyroid hormone, β-crosslinked C-telopeptide of type l collagen, were measured using an automated Roche electro-chemiluminescence system. BMD was measured using dual-energy X-ray absorptiometry. The association with age, BMD, 25-hydroxyvitamin D, parathyroid hormone, β-crosslinked C-telopeptide of type l collagen, and FGF21 levels were also evaluated in postmenopausal women. In nonfracture group and fragility fracture group, postmenopausal women's FGF21 level was 226.57pg/mL (149.11–354.43 pg/mL) and 219.43pg/mL (147.21–323.74 pg/mL), respectively. There is no significant difference in serum FGF21 levels between the fragility fracture group and the nonfracture group (p = 0.160). There was a significant statistical difference in BMD between the fragility fracture group and the nonfracture group (p?=?0.000). In multiple linear regression analysis, FGF21 levels were significantly positive associated with lumbar BMD in postmenopausal women (L1-4, p?=?0.007), independent of other factors, especially in fragility fracture group (L1-4, p?=?0.001). In addition, a significant positive association was also observed between serum FGF21 levels and age in postmenopausal women (p < 0.05). We reveal a positive correlation between serum FGF21 concentrations with lumbar BMD in Chinese Han postmenopausal women. No significant correlations are present between serum FGF21 and bone turnover marks or serum FGF21 and fragility fracture in our study.     

Serum Levels of a Cathepsin‐K Generated Periostin Fragment Predict Incident Low‐Trauma Fractures in Postmenopausal Women Independently of BMD and FRAX

Periostin is a matricellular protein involved in bone formation and bone matrix organization, but it is also produced by other tissues. Its circulating levels have been weakly associated with bone microstructure and prevalent fractures, possibly because periostin measured by the current commercial assays does not specifically reflect bone metabolism. In this context, we developed a new ELISA for a periostin fragment resulting from cathepsin K digestion (K‐Postn). We hypothesized that circulating K‐Postn levels could be associated with bone fragility. A total of 695 women (age 65.0 ± 1.5 years), enrolled in the Geneva Retirees Cohort (GERICO), were prospectively evaluated over 4.7 ± 1.9 years for the occurrence of low‐trauma fractures. At baseline, we measured serum periostin, K‐Postn, and bone turnover markers (BTMs), distal radius and tibia microstructure by HR‐pQCT, hip and lumbar spine aBMD by DXA, and estimated fracture probability using the Fracture Risk Assessment Tool (FRAX). Sixty‐six women sustained a low‐trauma clinical fracture during the follow‐up. Total periostin was not associated with fractures (HR [95% CI] per SD: 1.19 [0.89 to 1.59], p = 0.24). In contrast, K‐Postn was significantly higher in the fracture versus nonfracture group (57.5 ± 36.6 ng/mL versus 42.5 ± 23.4 ng/mL, p < 0.001) and associated with fracture risk (HR [95%CI] per SD: 2.14 [1.54 to 2.97], p < 0.001). After adjustment for aBMD, FRAX, bone microstructure, or BTMs, K‐Postn remained significantly associated with fracture risk. The performance of the fracture prediction models was improved by adding K‐Postn to aBMD or FRAX (Harrell C index for fracture: 0.70 for aBMD + K‐Post versus 0.58 for aBMD alone, p = 0.001; 0.73 for FRAX + K‐Postn versus 0.65 for FRAX alone, p = 0.005). Circulating K‐Postn predicts incident fractures independently of BMD, BTMs, and FRAX in postmenopausal women. Hence measurement of a periostin fragment resulting from in vivo cathepsin K digestion may help to identify subjects at high risk of fracture. © 2017 American Society for Bone and Mineral Research     

Randomized Controlled Trial of the Effects of Calcium With or Without Vitamin D on Bone Structure and Bone‐Related Chemistry in Elderly Women With Vitamin D Insufficiency

There are few data on the relative effects of calcium supplementation with or without extra vitamin D on BMD in patients selected for low vitamin D status. The aim of this study is to evaluate the relative importance of vitamin D and calcium treatment on BMD and bone‐related chemistry in elderly women with vitamin D insufficiency. Three hundred two elderly women (age, 77.2 ± 4.6 yr) with serum 25(OH)D concentrations <60 nM participated in a 1‐yr randomized, double‐blind, placebo‐controlled trial. All subjects received 1000 mg calcium citrate per day with either 1000 IU ergocalciferol (vitamin D₂) or identical placebo (control). The effects of time and time treatment interactions were evaluated by repeated‐measures ANOVA. At baseline, calcium intake was 1100 mg/d, and 25(OH)D was 44.3 ± 12.9 nM; this increased in the vitamin D group by 34% but not the control group after 1 year (59.8 ± 13.8 versus 45.0 ± 13.3 nM, p < 0.001). Total hip and total body BMD increased significantly, and procollagen type I intact N‐terminal propeptide (PINP) decreased during the study with no difference between the treatment groups (hip BMD change: vitamin D, +0.5%; control, +0.2%; total body BMD change: vitamin D, +0.4%; control, +0.4%; PINP change: vitamin D, ?3.9%; placebo, ?2.8%). Although the fasting plasma and urine calcium increased in both groups equally, there was no detectable change in serum PTH. The increase in 25(OH)D achieved with vitamin D supplementation had no extra effect on active fractional intestinal calcium absorption, which fell equally in both groups (vitamin D, ?17.4%; control, ?14.8%). In patients with a baseline calcium intake of 1100 mg/d and vitamin D insufficiency, vitamin D₂ 1000 IU for 1 year has no extra beneficial effect on bone structure, bone formation markers, or intestinal calcium absorption over an additional 1000 mg of calcium. Vitamin D supplementation adds no extra short‐term skeletal benefit to calcium citrate supplementation even in women with vitamin D insufficiency.     

Lack of association between the <Emphasis Type="Italic">Hind</Emphasis>III RFLP of the osteocalcin (BGP) gene and bone mineral density (BMD) in healthy pre- and postmenopausal Chinese women

In Caucasian populations, the polymorphic restriction endonuclease HindIII marker of the osteocalcin (also known as BGP, for bone Gla protein) gene has recently been reported to be associated with bone mass, a major risk determinant of osteoporosis. In this study, we investigated the relationship between the BGP HindIII polymorphism and bone mineral density (BMD) in 388 premenopausal (31.18 ± 5.92 years) and 169 postmenopausal (58.90 ± 6.27 years) Chinese women. The BMD of spine and hip was measured by dual-energy X-ray absorptiometry (DEXA). All the study subjects were genotyped at the HindIII site of the BGP gene by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) detecting methods. The BGP alleles were designated according to the absence (H) or presence (h) of the HindIII restriction site. We did not find any significant difference in spine and hip BMD across BGP genotypes in either pre- or postmenopausal women or the combined group. Our result is not consistent with recent reports that the HindIII marker of the BGP gene is associated with osteoporosis. The different findings may reflect inter-population differences in the association (i.e., linkage disequilibrium) of molecular markers with BMD, and indicate the limit of using the HindIII marker of the BGP gene as a genetic marker to discern women susceptible to low BMD and thus osteoporosis in Chinese.     

Differences in Macro‐ and Microarchitecture of the Appendicular Skeleton in Young Chinese and White Women

To identify the racial differences in macro‐ and microstructure of the distal radius and tibia that may account for the lower fracture rates in Asians than whites, we studied 61 healthy premenopausal Chinese and 111 white women 18–45 yr of age using high‐resolution pQCT (HR‐pQCT). The Chinese were shorter and leaner. Distal radius total cross‐sectional area (CSA) was 14.3% smaller in Chinese because of an 18.0% smaller trabecular area (p < 0.001). Cortical thickness was 8.8% greater in the Chinese, but cortical area was no different. Total volumetric BMD (vBMD) was 10.3% higher in the Chinese because of the 8.8% higher cortical thickness and 2.8% greater cortical density (all p < 0.01). Trabecular vBMD and bone volume/tissue volume (BV/TV) did not differ by race because trabeculae were 7.0% fewer but 10.8% thicker in Chinese than whites (both p < 0.01). Similar results were found at the distal tibia. Lower fracture risk in Chinese women may be partly caused by thicker cortices and trabeculae in a smaller bone‐more bone within the bone than in whites.     

Effects of Bazedoxifene on BMD and Bone Turnover in Postmenopausal Women: 2‐Yr Results of a Randomized,Double‐Blind,Placebo‐, and Active‐Controlled Study

Osteoporosis is an increasingly common health concern in postmenopausal women. In a 2‐yr phase III study, bazedoxifene prevented bone loss, reduced bone turnover, and was well tolerated in early postmenopausal women with normal or low BMD. Introduction : Bazedoxifene is a novel selective estrogen receptor modulator that has increased BMD and bone strength in experimental models, without stimulating breast or uterus. This 24‐mo, randomized, double‐blind study assessed the efficacy and safety of three doses of bazedoxifene compared with placebo and raloxifene in the prevention of postmenopausal osteoporosis. Materials and Methods : Healthy postmenopausal women with a BMD T‐score at the lumbar spine or femoral neck between –1.0 and ?2.5 or clinical risk factors for osteoporosis were randomly assigned to one of five groups: bazedoxifene 10, 20, or 40 mg/d, placebo, or raloxifene 60 mg/d. All women received elemental calcium. Efficacy outcomes included changes from baseline through 24 mo in BMD of the lumbar spine, hip, femoral neck, and femoral trochanter and biomarkers of bone metabolism. Results : The intent‐to‐treat population included 1434 women (mean age, 58 yr; mean time from last menstrual period, 11 yr). All doses of bazedoxifene and raloxifene prevented bone loss, whereas in the placebo group, there was significant loss of BMD at all skeletal sites. Mean differences in percent change in lumbar spine BMD from baseline to 24 mo relative to placebo were 1.08 ± 0.28%, 1.41 ± 0.28%, 1.49 ± 0.28%, and 1.49 ± 0.28% for 10, 20, and 40 mg bazedoxifene and 60 mg raloxifene, respectively (p < 0.001 for all comparisons). Comparable BMD responses were observed at other body sites. Significant and comparable decreases in serum osteocalcin and C‐telopeptide levels from baseline and relative to placebo with active treatment were observed as early as 3 mo and were sustained through study conclusion (p < 0.001). Overall incidences of adverse events, serious adverse events, and discontinuations caused by adverse events were similar between groups. The most common adverse events included headache, infection, arthralgia, pain, hot flush, and back pain. Conclusions : Treatment with bazedoxifene prevented bone loss and reduced bone turnover equally as well as raloxifene and was generally well tolerated in postmenopausal women with normal/low BMD.     

Finite Element Analysis Based on In Vivo HR‐pQCT Images of the Distal Radius Is Associated With Wrist Fracture in Postmenopausal Women

BMD, bone microarchitecture, and bone mechanical properties assessed in vivo by finite element analysis were associated with wrist fracture in postmenopausal women. Introduction: Many fractures occur in individuals with normal BMD. Assessment of bone mechanical properties by finite element analysis (FEA) may improve identification of those at high risk for fracture. Materials and Methods: We used HR‐pQCT to assess volumetric bone density, microarchitecture, and μFE‐derived bone mechanical properties at the radius in 33 postmenopausal women with a prior history of fragility wrist fracture and 33 age‐matched controls from the OFELY cohort. Radius areal BMD (aBMD) was also measured by DXA. Associations between density, microarchitecture, mechanical parameters and fracture status were evaluated by univariate logistic regression analysis and expressed as ORs (with 95% CIs) per SD change. We also conducted a principal components (PCs) analysis (PCA) to reduce the number of parameters and study their association (OR) with wrist fracture. Results: Areal and volumetric densities, cortical thickness, trabecular number, and mechanical parameters such as estimated failure load, stiffness, and the proportion of load carried by the trabecular bone at the distal and proximal sites were associated with wrist fracture (p < 0.05). The PCA revealed five independent components that jointly explained 86.2% of the total variability of bone characteristics. The first PC included FE‐estimated failure load, areal and volumetric BMD, and cortical thickness, explaining 51% of the variance with an OR for wrist fracture = 2.49 (95% CI, 1.32–4.72). Remaining PCs did not include any density parameters. The second PC included trabecular architecture, explaining 12% of the variance, with an OR = 1.82 (95% CI, 0.94–3.52). The third PC included the proportion of the load carried by cortical versus trabecular bone, assessed by FEA, explaining 9% of the variance, and had an OR = 1.61 (95% CI, 0.94–2.77). Thus, the proportion of load carried by cortical versus trabecular bone seems to be associated with wrist fracture independently of BMD and microarchitecture (included in the first and second PC, respectively). Conclusions: These results suggest that bone mechanical properties assessed by μFE may provide information about skeletal fragility and fracture risk not assessed by BMD or architecture measurements alone and are therefore likely to enhance the prediction of wrist fracture risk.     

Association of Muscle Weakness With Post‐Fracture Mortality in Older Men and Women: A 25‐Year Prospective Study

Osteoporotic fracture increases the risk of premature mortality. Muscle weakness is associated with both increased fracture risk and low bone mineral density (BMD). However, the role of muscle strength in post‐fracture mortality is not well understood. This study examines the change of muscle strength measured at quadriceps (QS) before and after fracture and defines the relationship between muscle strength and post‐fracture mortality. The study involved 889 women and 295 men (who were participating in the Dubbo Osteoporosis Study) who had at least one low‐trauma fracture (ascertained from X‐ray reports) after the age of 50 years. Median follow‐up time was 11 years (range 1 to 24). To determine the change in muscle strength before and after a fracture, we selected a subset of 344 women and 99 men who had had at least two muscle strength measurements before the fracture event and a subset of 407 women and 105 men who had had at least two measurements after the fracture. During the follow‐up period, 366 (41.2%) women and 150 (50.9%) men died. The annual rate of decrease in height‐adjusted muscle strength before fracture was 0.27 kg/m (1.85%) in women and 0.40 kg/m (1.79%) in men. Strength loss after fracture was not significantly different from that before fracture. In women, after adjusting for baseline age and BMD, each SD (5 kg/m) lower height‐adjusted pre‐ and post‐fracture quadriceps strength was associated with a 27% (hazard ratio [HR] = 1.27; 95% confidence interval [CI] 1.07, 1.50) and 18% (HR = 1.18; 95% CI 1.01, 1.38) increase in post‐fracture mortality risk, respectively. Similarly, in men, each SD (5 kg/m) lower height‐adjusted pre‐ and post‐fracture QS was associated with increased mortality before fracture (HR = 1.33; 95% CI 1.09, 1.63) and after fracture (HR = 1.43; 95% CI 1.16, 1.78). Muscle weakness accounted for 15% (95% CI 0.05, 0.24) of premature deaths after fracture in women and 23% (95% CI 0.11, 0.35) in men. These results indicate that in the older individuals, lower muscle strength is an independent risk factor for post‐fracture mortality. © 2017 American Society for Bone and Mineral Research.